This program is designed to develop methods for the functionalization and assembly of nitrogen heterocycles that are common subunits of cytotoxic agents. The approach involves the development of new techniques for carbon- carbon bond formation using mechanistic concepts. The techniques are studied at the fundamental level to evaluate the interplay between electronic factors and reactivity. When these issues are sufficiently understood, the methods are applied to the synthesis of families of cytotoxic agents. Targets for the next grant period include (1) cytochalasins D, H, and analogs potentially capable of HIV protease inhibition, (2) aziridinomitosenes and the diketo tautomers of the leucoaziridinomitosene family, structures that are responsible for the antitumor activity of mitomycins. (3) the tricyclic skeleton of makaluvamines, the recently discovered inhibitors of topoisomerase II, and (4) diazonamide A, a cytotoxic macrocyclic oxazole-peptide hybrid derived from marine organisms. Since the receptor-substrate complexes for most of these cytotoxic agents are not well-defined, the approach will be to submit synthetic intermediates and analogs for broad screening at the NCI Drug Synthesis and Chemistry Branch. Fundamental technologies to be investigated during the next grant period include (1) Lewis acid mediated coupling of 2-metalated oxazoles. (2) internal trapping of azomethine ylides derived from oxazolium salts and 4- oxazolines, (3) aziridine functionalization via 2-lithio or 2-stannyl derivatives. (4) activation of C-Sn bonds for Stille coupling using deoxastannatrane reagents. (5) intramolecular organometallic coupling of activated aziridines to assemble the aziridinomitosene. and (6) peptide bond assembly using amidines as agents for nitrogen activation.